This application is the United States National Phase Application under 35 USC 371 of International Application PCT/JP99/04017 (not published in English) filed Jul. 27, 1999.
The present invention relates to novel thiazolidine derivatives which are useful as drugs such as chymase inhibitors.
Compounds having a thiazolidine ring as a main skeleton is known to be useful for various drugs, and many derivatives thereof have also been synthesized. Main synthesis studies are as follows; a study of converting 4-thiazolidinecarboxylic acid, which can be synthesized easily, into amide compounds; and a study of introducing various substituents into the nitrogen atom at the 3rd-position through a carbonyl linkage. For example, it was reported that carboxylic acid derivatives were further introduced into the amide linkage at the 4th-position through an alkylene chain (see Japanese Laid-open Patent Publication No. 49373/1981 and Japanese Laid-open Patent Publication No. 139455/1981). Many studies were also reported wherein the various substituents are introduced into the nitrogen at the 3rd-position through the carbonyl linkage. However, compounds wherein the nitrogen atom joins with the carbonyl through an alkylene chain have scarcely been studied.
There are still many unknown compounds in the compounds having a thiazolidine ring as the main skeleton, and preparation of novel compounds and a study of their pharmacological actions are very interesting subjects.
The present inventors studied preparation of various novel compounds derived from 4-thiazolidinecarboxylic acid. They focused attention on synthesis of novel compounds wherein 1) the carboxyl group at the 4th-position is amidated and the resulting amide moiety is substituted by substituents having a carbonyl group through an alkylene chain, and further 2) various substituents are introduced into the nitrogen atom at the 3rd-position through a carbonyl group. In particular, their efforts were focused on selection of substituents joining with the carbonyl group through an alkylene chain as the substituents introduced into the nitrogen atom at the 3rd-position through the carbonyl group. As a result, the present inventors succeeded in preparing many novel compounds as mentioned later. Studying their pharmacological actions, these novel compounds were found to have chymase inhibitory actions and to be useful as drugs. In a process of the synthesis of the above-mentioned novel thiazolidine derivatives, the present inventors succeeded also in preparing novel compounds which are useful as synthetic intermediates of the derivatives.
The present invention relates to compounds represented by the following general formula [I] and salts thereof (hereinafter referred to as xe2x80x9cthe present compoundsxe2x80x9d as far as there is no proviso), pharmaceutical compositions containing the present compound or the salt thereof as an active ingredient, and compounds which are represented by the following general formula [II] and are useful as synthetic intermediates of the present compounds and salts thereof (hereinafter referred to as xe2x80x9cthe present synthetic intermediatesxe2x80x9d as far as there is no proviso). 
wherein R1 is lower alkyl, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, phenyl, phenyl-lower alkyl, phenyl-lower alkoxy, phenoxy, phenoxy-lower alkyl, amino, lower alkylamino or a nonaromatic heterocycle.
R2 is hydrogen or lower alkyl, and R2 can join with A1 through carbon or sulfur to form a nonaromatic heterocycle.
R3 is hydrogen, lower alkyl or phenyl, and R3 can join with A1 through carbon to form a nonaromatic heterocycle.
R4 is hydrogen or lower alkyl.
R5 is lower alkyl, halogeno-lower alkyl, hydroxy, lower alkoxy, phenyl, phenyl-lower alkoxy, phenoxy, carboxyl, lower alkoxy-carbonyl, phenyl-lower alkoxycarbonyl or an aromatic heterocycle.
A1 is lower alkylene, wherein the lower alkylene can be substituted by hydroxy, lower alkoxy, phenyl, phenoxy, carboxyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or an aromatic heterocycle.
A2 is lower alkylene, wherein the lower alkylene can be substituted by phenyl.
Each nonaromatic heterocycle defined above can be substituted by lower alkyl, phenyl, phenyl-lower alkyl, amino, lower alkylamino or phenyl-lower alkylamino.
Each phenyl ring of phenyl, phenyl-lower alkyl, phenyl-lower alkoxy, phenoxy, phenoxy-lower alkyl and phenyl-lower alkoxycarbonyl defined above can be substituted by halogen, lower alkyl, hydroxy, lower alkoxy, phenyl, phenoxy, carboxyl, lower alkoxycarbonyl, amino, lower alkylamino, nitro or cyano.
Each lower alkyl moiety of lower alkylamino defined above can be substituted by phenyl, amino or lower alkylamino. The same definitions are applied hereinafter.
The groups defined above are hereinafter described in detail.
The halogen is fluorine, chlorine, bromine or iodine.
The lower alkyl is straight-chain or branched alkyl having one to six carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl or tert-butyl.
The lower alkoxy is straight-chain or branched alkoxy having one to six carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy or tert-butoxy.
The lower alkylene is straight-chain or branched alkylene having one to six carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, propylmethylene, isopropylmethylene, butylmethylene, isobutylmethylene, sec-butylmethylene, tert-butylmethylene, dimethylethylene, ethylethylene, propylethylene, isopropylethylene, methyltrimethylene or propylene.
The nonaromatic heterocycle is a nonaromatic heterocycle selected from pyrrolidine, piperidine, homopiperidine, octahydroazocine, pyrroline, piperazine, imidazolidine, imidazoline, pyrazolidine, pyrazoline, oxazolidine, thiazolidine and the like.
The aromatic heterocycle is an aromatic heterocycle selected from pyrrole, indole, isoindole, imidazole, pyrazole, oxazole, isoxazole, benzoxazole, thiazole, isothiazole, benzothiazole, pyridine, quinoline, pyrazine and the like.
The lower alkylamino is mono- or di-lower alkylamino.
Nitrogen atom of the above-mentioned amino, lower alkylamino, nonaromatic heterocycle or aromatic heterocycle can be protected with a protecting group. This protecting group can be a general protecting group of nitrogen atom of amino, lower alkylamino, a nonaromatic heterocycle or an aromatic heterocycle, such as acyl, substituted lower alkyl or substituted sulfonyl.
In detail, examples of the protecting group are acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl, lower alkoxycarbonyl, halogeno-lower alkoxycarbonyl, phenylcarbonyl, phenyl-lower alkoxycarbonyl or phenoxycarbonyl, substituted alkyl such as phenyl-lower alkyl, phenyl-lower alkoxy-lower alkyl or trityl, and substituted sulfonyl such as lower alkylsulfonyl or phenylsulfonyl. Each phenyl ring of the phenylcarbonyl, the phenyl-lower alkoxycarbonyl, the phenoxycarbonyl, the phenyl-lower alkyl, the phenyl-lower alkoxy-lower alkyl, the trityl and the phenylsulfonyl can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
Specific examples of the protecting group are acyl such as formyl, acetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzoyl, benzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or phenoxycarbonyl, substituted alkyl such as benzyl, 2-nitrobenzyl, benzyloxymethyl or trityl, and substituted sulfonyl such as methanesulfonyl, benzenesulfonyl or toluenesulfonyl.
Salts in the present invention refer to any pharmaceutically acceptable salts. Examples thereof are salts with an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid, salts with an organic acid such as acetic acid, fumaric acid, maleic acid or tartaric acid, salts with an alkali metal or an alkaline-earth metal such as sodium, potassium or calcium, and the like. When the present compounds or the present intermediates have asymmetric carbon atoms and geometrical isomers or optical isomers are present in the present compounds or the present intermediates, these isomers are also included in the scope of the present invention. The present compounds or the present intermediates can be in the form of solvates such as hydrates.
Preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof;
(1a) R1 is a group selected from lower alkyl, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, phenyl, phenyl-lower alkyl, phenyl-lower alkoxy, phenoxy, phenoxy-lower alkyl, amino, lower alkylamino, piperidine and piperazine, wherein each phenyl ring of phenyl, phenyl-lower alkyl, phenyl-lower alkoxy, phenoxy or phenoxy-lower alkyl defined above can be substituted by halogen or a group selected from lower alkyl, Lower alkoxy and nitro, the lower alkyl moiety of the lower alkylamino can be substituted by a group selected from phenyl and amino, and the piperidine or the piperazine can be substituted by a group selected from lower alkyl and lower alkylamino; and/or
(2a) R2 is hydrogen or lower alkyl; and/or
(3a) R2 is a group joining with A1 through carbon or sulfur to form a ring selected from pyrrolidine and thiazolidine; and/or
(4a) R3 is hydrogen or phenyl, wherein the phenyl can be substituted by halogen or a group selected from, lower alkyl, lower alkoxy and nitro; and/or
(5a) R3 is a group joining with A1 through carbon to form a ring selected from pyrrolidine, piperidine, homopiperazine and octahydroazocine; and/or
(6a) R4 is hydrogen; and/or
(7a) R5 is a group selected from lower alkyl, halogeno-lower alkyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, oxazole, benzoxazole, thiazole and benzothiazole; and/or
(8a) A1 is lower alkylene which can be substituted by a group selected from hydroxy, lower alkoxy, phenyl, carboxyl, lower alkoxycarbonyl, indole and imidazole; and/or
(9a) A2 is lower alkylene which can be substituted by phenyl.
Namely,
Compounds defined by above (1a) in the compounds represented by the general formula [I],
Compounds defined by above (2a) in the compounds represented by the general formula [I],
Compounds defined by above (3a) in the compounds represented by the general formula [I],
Compounds defined by above (4a) in the compounds represented by the general formula [I],
Compounds defined by above (5a) in the compounds represented by the general formula [I],
Compounds defined by above (6a) in the compounds represented by the general formula [I],
Compounds defined by above (7a) in the compounds represented by the general formula [I],
Compounds defined by above (8 a) in the compounds represented by the general formula [I],
Compounds defined by above (9a) in the compounds represented by the general formula [I], and
Compounds defined by any combinations of two or more of above (1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a) and (9a) in the compounds represented by the general formula [I].
More preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof; (1b) R1 is a group selected from lower alkoxy, lower alkoxy-lower alkyl, phenyl-lower alkoxy, phenoxy-lower alkyl, lower alkylamino and piperidine, wherein the phenyl ring of the phenyl-lower alkoxy can be substituted by lower alkoxy, the lower alkyl moiety of the lower alkylamino can be substituted by phenyl or amino, and the piperidine can be substituted by lower alkylamino; and/or
(2b) R2 is hydrogen; and/or
(3b) R2 is a group joining with A1 through carbon to form pyrrolidine; and/or
(4b) R3 is hydrogen or phenyl; and/or
(5b) R3 is a group joining with A1 through carbon to form a ring selected from piperidine and homopiperazine; and/or
(6b) R4 is hydrogen; and/or
(7b) R5 is lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl; and/or
(8b) A1 is lower alkylene which can be substituted by hydroxy or indole; and/or
(9b) A2 is lower alkylene which can be substituted by phenyl.
Namely,
Compounds defined by above (1b) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (2b) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (3b) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (4b) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (5b) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (6b) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (7b) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (8b) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (9b) in the compounds represented by the general formula [I] and salts thereof, and
Compounds defined by any combinations of two or more of above (1b), (2b), (3b), (4b), (5b), (6b), (7b), (8b) and (9b) in the compounds represented by the general formula [I] and salts thereof.
Further preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof;
(1c) R1 is a group selected from methyl, tert-butoxy, methoxymethyl, phenylmethyl, phenylethyl, phenylmethoxy, (4-chlorophenyl)methoxy, (4-methylphenyl)methoxy, (4-methoxyphenyl)methoxy, (4-nitrophenyl)methoxy, phenoxy, phenoxymethyl, ethylmethylamino, N-methyl-N-phenylmethylamino, N-(2-aminoethyl)-N-methylamino, 4-(methylamino)piperidino and 4-methylpiperazino; and/or
(2c) R2 is hydrogen or methyl; and/or
(3c) R2 is a group joining with A1 through carbon or sulfur to form a ring selected from pyrrolidine and thiazolidine; and/or
(4c) R3 is a group selected from hydrogen, phenyl, 4-chlorophenyl, 4-methylphenyl,4-methoxyphenyl and 4-nitrophenyl; and/or
(5c) R3 is a group joining with A1 through carbon to form a ring selected from pyrrolidine, piperidine, homopiperazine and octahydroazocine; and/or
(6c) R4 is hydrogen; and/or
(7c) R5 is a group selected from trifluoromethyl, isopropoxycarbonyl, benzyloxycarbonyl, oxazolyl, benzoxazolyl, thiazolyl and benzothiazolyl; and/or
(8c) A1 is a group selected from methylene, methylmethylene, ethylmethylene, isopropylmethylene, isobutylmethylene, Sec-butylmethylene, tert-butylmethylene, phenylmethylene, phenylmethylmethylene, (4-phenylbutyl)methylene, (4-hydroxyphenyl)methylmethylene, [(3-indolyl)methyl]methylene, [(5-imidazolyl)methyl]methylene, (hydroxymethyl)methylene, (tert-butoxymethyl)methylene and (carboxylmethyl)methylene; and/or
(9c) A2 ismethylene or phenylmethylmethylene.
Namely,
Compounds defined by above (1c) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (2c) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (3c) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (4c) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (5c) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (6c) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (7c) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (8c) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (9c) in the compounds represented by the general formula [I] and salts thereof, and
Compounds defined by any combinations of two or more of above (1c), (2c), (3c), (4c), (5c), (6c), (7c), (8c) and (9c) in the compounds represented by the general formula [I] and salts thereof.
The most preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof;
(1d) R1 is a group selected from tert-butoxy, methoxymethyl, phenylmethoxy, (4-methoxyphenyl)methoxy, phenoxymethyl, ethylmethylamino, N-methyl-N-(phenylmethyl)amino, N-(2-ethylamino)N-methylamino and (4-methylamino)piperidino; and/or
(2d) R2 is hydrogen; and/or
(3d) R2 is a group joining with A1 through carbon to form pyrrolidine; and/or
(4d) R3 is hydrogen or phenyl; and/or
(5d) R3 is a group joining with A1 through carbon to form a ring selected from piperidine and homopiperazine; and/or
(6d) R4 is hydrogen; and/or
(7d) R5 is a group selected from isopropoxycarbonyl and (phenylmethoxy)carbonyl; and/or
(8d) A1 is a group selected from methylene, methylmethylene, ethylmethylene, isopropylmethylene, isobutylmethylene, sec-butylmethylene, tert-butylmethylene, [(5-imidazolyl)methyl]methylene, (hydroxymethyl)methylene and (tert-butoxymethyl)methylene.
(9d) A2 is phenylmethylmethylene.
Namely,
Compounds defined by above (1d) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (2d) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (3d) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (4d) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (5d) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (6d) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (7d) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (8d) in the compounds represented by the general formula [I] and salts thereof,
Compounds defined by above (9d) in the compounds represented by the general formula [I] and salts thereof, and
Compounds defined by any combinations of two or more of above (1d), (2d), (3d), (4d), (5d), (6d), (7d), (8d) and (9d) in the compounds represented by the general formula [I] and salts thereof.
Since the present synthetic intermediate is selected corresponding to the chemical structure of the present compound, preferred examples of the present synthetic intermediate are also selected corresponding to the preferred examples of the present compound.
A typical synthesis route scheme of the present compound is shown below. 
The present compound [I] can be synthesized, for example, through the synthesis route represented by the above reaction route scheme. However, this synthesis route exemplifies a typical route and does not show all methods.
This synthesis method is described in detail below.
Carboxyl group of the carboxylic acid derivative [III] is activated with a mixed acid anhydride-producing reagent (for example, isobutyl chloroformate). The acid derivative [III] is condensed with the 1,3-thiazolidinecarboxylic acid derivative [IV] in the presence of a base to convert it into the compound represented by the formula [V]. This compound [V] is reacted with the amino alcohol derivative [VI] using a condensing agent (for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) to give the present synthetic intermediate represented by the formula [II]. Then, this synthetic intermediate [II] is reacted with dimethyl sulfoxide activated with acetic anhydride to oxidize hydroxy of the synthetic intermediate [II] to give the present compound [I].
In the above-mentioned synthesis method, when the reactant has a hydroxy or amino group in its molecule, these groups can be protected with suitable protecting groups, if necessary, and these protecting groups can also be removed by the conventional method after reaction. When the reactant has a carboxyl group in its molecule, the carboxyl group can be esterified, if necessary, and the ester can also be converted into a carboxylic acid by hydrolysis.
When R3 joins with A1 through carbon to form the nonaromatic heterocycle in the present compounds, the target products can be synthesized by a method similar to the above synthesis route by using the bicyclic carboxylic acid derivatives [VII] shown below instead of the compound [V]. These bicyclic carboxylic acid derivatives can be synthesized by Reference Examples described later. 
[wherein xe2x80x9cnxe2x80x9d is 1 to 4.]
The compounds obtained by the above-mentioned method can be converted into the above-mentioned salts by the conventional method. The diastereo isomers and the optical isomers are present in the above-mentioned compounds represented by the general formula, and all of them are included in the present invention. When an optically active starting material is used, a single diastereo isomer and a single optical isomer are obtained. When racemate is used as a starting material, respective isomers can be separated by the conventional method, for example, by a method of using optical resolution or the like.
As described in the part of xe2x80x9cBackground Artxe2x80x9d, various compounds having a thiazolidine ring as a main skeleton are known to be used for drugs. 
However, the present compounds are novel compounds being unknown in literatures. As shown in the above formula [VIII], features of their chemical structure composing a main skeleton are as follows. 1) First, the carboxyl group at the 4th-position of 4-thiazolidinecarboxylic acid is amidated, and the various substituents xe2x80x9cAxe2x80x9d having a carbonyl group such as lower alkoxycarbonyl and aromatic heterocycles are introduced into the amide moiety through the xe2x80x9calkylenexe2x80x9d, and 2) the various substituents [Bxe2x80x94(CO)xe2x80x94N(xcx9c)-alkylene-] are introduced into the nitrogen atom at the 3rd-position of 4-thiazolidinecarboxylic acid through a carbonyl group. Focusing attention on these two points and studying precisely, the present inventors have succeeded in preparing the many novel compounds.
Administration methods of drugs can be a method of administering active compounds themselves or a method of administering the drugs in the form to be decomposed in vivo and to be converted into the active compounds, namely in the form of prodrugs. Both are widely used. The present compounds also have a carboxyl group in their molecule. The present compounds can be administered in the form of the carboxylic acid and also in the form of an ester which can be converted into the carboxylic acid by hydrolysis. When the present compounds have an amino group in their molecule, the present compounds can be administered with the amino group protected with a suitable protecting group.
Further, in order to find utility of the present compounds, chymase inhibitory effects of the present compounds were studied. Details will be described later in the part of xe2x80x9cPharmacological Testxe2x80x9d. The present compounds exhibited excellent chymase inhibitory effects. Chymase has been reported to exist in systemic tissues such as gut, skin and lung centering around tissues of cardiovascular system and to participate in outbreaks of physiologic functions such as cardiovascular lesion, inflammation, immune functions and tissue remodeling (Journal of Clinical and Experimental Medicine, 172 (9), 559 (1995)). Chymase has been reported to participate also in outbreaks of cardiac infarction, heart failure, blood-vessel restenosis after PTCA and the like (Blood Vessel and Endothelium,5 (5), 37 (1995)), hypertension (FEBS Lett., 406, 301(1997)), diabetes complication (Biol. Chem., Hoppe Seyler (GERMANY, WEST), 369 Suppl., p299), allergic diseases (Nobuhiko Katsunuma, xe2x80x9cIntracellular Proteolysisxe2x80x9d, p. 101-106), asthma (J. Pharmacol. Exp. Ther., 244 (1), 133 (1987)) and the like. Chymase inhibitors are expected to be effective in treating these diseases.
The present compound can be administered orally or parenterally. Examples of dasage forms are tablets, capsules, granules, powders, injections, eyedrops and the like. The present compound can be formulated into preparations by the conventional methods. For example, oral preparations such as tablets, capsules, granules and powders can be produced by adding optionally diluents such as lactose, crystalline cellulose, starch and vegetable oil; lubricants such as magnesium stearate and talc; binders such as hydroxypropylcellulose and polyvinyl pyrrolidone; disintegrator such as calcium carboxymethylcellulose or low-substituted hydroxypropylmethylcellulose; coating agent such as hydroxypropylmethylcellulose, macrogol or silicone resin; or film forming agent such as gelatin film. Eyedrops can be produced, if necessary, by adding isotonic agents such as sodium chloride and concentrated glycerine; buffers such as sodium phosphate and sodium acetate; surfactants such as polyoxyethylenesorbitan monooleate, polyoxyl 40 stearate and polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and disodium edetate; preservatives such as benzalkonium chloride and paraben; and the like. pH can be in a range acceptable for ophthalmic preparations, and it is more preferably in a range of 4 to 8.
The dosage of the present compound can be selected suitably according to the symptom, age, dosage form and the like. In case of the oral preparation, the present compound can be administered once to several times per day with a daily dose of 0.1 to 5000 mg, preferably 1 to 1000 mg.